The Pathobiology of "Autosomal Dominant"

Have you ever wondered why certain traits are autosomal dominant and others are autosomal recessive?

In most cases, the explanation is fairly straightforward. Diseases, such as Huntington's or myotonic dustrophy, which are transmitted in an autosomal dominant fashion are mostly due to the toxic effect of the mutant protein encoded by the abnormal gene. This protein builds up inside the endoplasmic reticulum and interferes with the synthesis of other vital proteins, which then leads to the abnormal phenotype.

With autosomal recessive inheritance, it is usually an useful function that is lost. Both alleles encoding an essential protein are lost, and thus the product can no longer be synthesised, for e.g. the CFTR protein in cystic fibrosis.

There are notable exceptions to this general principle. Sometimes, the product of one normal allele is insufficient to perform the requisite function of the putative gene. This is called haploinsufficiency. Thus, the condition is transmitted as autosomal dominant, with a dose-response gradient between those heterozygous and homozygous for the abnormal allele. Examples of haploinsufficiency contributing to autosomal dominant transmission are dyskeratosis congenita, Williams syndrome and autosomal dominant retinitis pigmentosa. Marfans and Ehlers Danlos syndromes are also inherited in a similar way.

A different, but nonetheless fascinating mechanism of autosomal dominant inheritance is illustrated by an autoinflammatory condition called TRAPS (TNF Receptor Associated Periodic Syndrome). In this syndrome, the 55 kDa TNF receptor on the cell surface is abnormal, and does not shed on binding to the pro-inflammatory cytokine TNF alpha. Thus prolonged signalling through TNF alpha leads to an augmented inflammatory response, with excessive production of NF-kappa B. Further, it is thought that the usual neutralising effect of circulating "soluble" (non-membrane bound) TNF receptor on TNF alpha is reduced.

The TNF alpha receptor is homotrimeric, i.e. it is composed of three similar units. Most subjects with TRAPS have only 1 abnormal allele, usually due to a missense mutation, while the other allele is normal. However, assuming that even one mutated component of the trimer would lead to abnormal receptor function, one can see that even with one normal allele, 7 out of 8 receptors would be abnormal (the odds are only 1 in 2^3 that in a given trimeric receptor, all 3 components would be from the normal allele). Thus, the condition would transmit as autosomal dominant.

The Problem of Isolated Uveitis

One of the most common reasons for referral to the Rheumatologist from the Ophthalmologist is the young subject with recurrent or troublesome episodes of uveitis, often in association with a positive ANA or other features suggestive of an autoimmune aetiology such as a raised ACE. The query is whether such subjects have an underlying systemic disease contributing to their uveitis. Certain features can help narrow down the D/D.

1. HLA B27 associated spondarthritis presents with acute unilateral anterior uveitis that improves within 3 months but often recurs in the other eye. Therefore simultaneous or closely spaced occurrence of uveitis in both eyes is not characteristic of this condition, even if arthralgias are present. Prognosis is excellent.
2. The uveitis associated with IBD is often more chronic, posterior to the lens, and bilateral and more common in women. In subjects with IBD, the uveitis often presents prior to bowel symptoms (10/17 in one series).
3. Anterior uveitis is associated with the presence of deposits on the back of the cornea, called keratic precipitates (KP). In the case of sarcoidosis, these KPs are often large and greasy, therefore fine keratic precipitates make sarcoid unlikely.
4. The uveitis of sarcoid is often chronic, bilateral, posterior as well as anterior and unaccompanied by systemic features.
5. Syphilitic uveitis may not be accompanied by systemic features, In Asians, always rule out tuberculosis.
6. In subjects above the age of 45 with chronic posterior uveitis, rule out lymphoma, particularly DLBCL type of NHL. Higher risk in HIV positive cases. Thus, lymphoma is an uveitis mimic.
7. In children with JIA, uveitis is more common in those with oligoarticular arthritis and positive ANA. Polyarticular involvement and absence of ANA are less commonly associated with arthritis.
8. Behcet's disease often causes a panuveitis, is often associated with retinal vasculitis, is silent, and thus can lead to blindness. It's important to be aware that while anterior uveitis presents with pain, redness, photophobia, headache or brow pain and constricted pupils, posterior uveitis presents with a white eye, is silent, and can only be picked up initially by the presence of vitreous cells on slit lamp examination. Being silent, it can lead to blindness, and therefore needs a high index of suspicion. This is also true for children with JIA.
9. Multiple sclerosis can be associated with pars planitis (intermediate uveitis).
10. TINU or Tubulointerstitial Nephritis with Uveitis is a rare condition that combines uveitis with interstitial nephritis. It can be sen in subjects with Sjogren's syndrome or sarcoid.
11. Other autoimmune conditions that present less commonly with uveitis are SLE and GPA (Wegener's).